The purpose of the proposed study, Genetics of Coronary and Aortic Calcification (GENCAC), is to identify genetic factors that establish susceptibility to coronary and aortic atherosclerosis and to the hyperinflammatory host response. We propose to quantify coronary and aortic artery calcium volume in 441 informative pedigrees (3,000 individuals) previously examined and extensively genotyped (-400 markers spanning the genome) by the NHLBI Family Heart Study, in order to identify genes associated with atherosclerosis. An additional 275 African American sibships (-600 individuals) will be examined to address these study questions in this high-risk population. Inflammatory cytokines and markers of the inflammatory response will be measured, to characterize both the inflammatory burden, and the host response. Interindividual variability in the inflammatory host response, and the extensive metabolic, behavioral, and environmental data collected on these pedigrees in the FHS will provide enhanced phenotypic homogeneity and increased analytic power in assessing the genetic basis of atherosclerosis. Novel laboratory methodology and state of the art statistical methods will be used to find, localize and characterize the influence of predisposing genes to atherosclerosis and the inflammatory host response, with attention to phenotypic, genetic and population heterogeneity, epistasis, complex interactions among the genetic and environmental risk factors, and the detection of genomic regions affecting phenotypic susceptibility. The cost-efficient design of this study will be based on sibships and large pedigrees, all of whom have been examined and have genome scan data available. This study will contribute new information on genetic variation, and context-dependent effects associated with susceptibility to atherosclerosis which is the number one cause of death in the U.S. and is the primary driver of health care expenditures in our society. This application corresponds to the Arterial Calcium Reading Center submitted by Wake Forest University School of Medicine as part of the GENCAC genetic epidemiology network.